Second Generation Antibiotics from Ethambutol

乙胺丁醇（EMB）是在20世纪50年代后期由Lederle实验室从大约2000种大多数对称的二胺中开发出来的。乙胺丁醇是一种理想的小分子药物，可以通过组合化学进行优化：它具有低毒性和良好的药代动力学，但相对较高的药物浓度为5 mg/ml，可以通过额外的模拟和药物化学显着提高。我们设计了固相合成与乙胺丁醇相关的不对称1，2-二胺的方案，并使用该方案合成100，000种结构类似物的测试文库。该文库已经使用对细胞壁抑制反应阳性的全细胞荧光素酶系统和使用用于测定针对结核分枝杆菌的MIG的微量肉汤稀释测定来筛选。从该程序中，我们得到了约300个离散命中，其在两种测定中均显示出活性。我们建议扩展的结构多样性，特别强调在第一个库中代表性不足的分子类，以及围绕可行的命中额外的类比，由这个库。药物化学将受到SAR和肠道吸收可能性的指导。我们提出了一系列的生化分析，这将使我们能够优先打击分子，并确认这些分子有一个共同的目标，以促进SAR的解释。这些试验将扩展至包括相关电极导线系列的初步药理学和药代动力学分析。我们将进一步建立体内筛选系统，使我们能够将适当的命中系列推进到结核病的小动物模型中。这些研究应该使我们能够确定最终将在人类中进行疗效评估的候选药物。

Ethambutol (EMB) was developed at Lederle Laboratories in the late 1 950s from a collection of about 2000 mostly symmetrical diamines. Ethambutol is an ideal small-molecule drug to be optimized by combinatorial chemistry: it has low toxicity and good pharmacokinetics, but a relatively high MIG of 5 mg/ml that could be dramatically improved through additional analoging and medicinal chemistry. We have devised a protocol for solid-phase synthesis of asymmetric 1 ,2- diamines related to ethambutol and used this protocol to synthesize a test library of 100,000 structural analogs. This library has been screened using both a whole-cell luciferase system that responds positively to cell- wall inhibition and using microbroth dilution assays for the determination of MIGs against Mycobacterium tuberculosis. From this procedure we arrived at approximately 300 discrete hits that show activity in both assays. We propose to extend the structural diversity represented-by this library with particular emphasis on classes of molecules underrepresented in the first library as well as additional analoging around viable hits. Medicinal chemistry will be guided by both SAR and likelihood of intestinal absorption. We propose a series of biochemical analyses that will allow us to prioritize hit molecules and confirm that these molecules share a common target in order to facilitate interpretation of SAR. These assays will be extended to include preliminary pharmacologic and pharmacokinetic analysis of related lead series. We will further establish in vivo screening systems that will allow us to move appropriate hit series forward into small animal models of tuberculosis. These studies should allow us to identify candidates that will ultimately be evaluated for efficacy in humans.